| Literature DB >> 29894693 |
Ewa Gogola1, Alexandra A Duarte1, Julian R de Ruiter2, Wouter W Wiegant3, Jonas A Schmid4, Roebi de Bruijn2, Dominic I James5, Sergi Guerrero Llobet6, Daniel J Vis7, Stefano Annunziato1, Bram van den Broek8, Marco Barazas1, Ariena Kersbergen9, Marieke van de Ven10, Madalena Tarsounas11, Donald J Ogilvie5, Marcel van Vugt6, Lodewyk F A Wessels7, Jirina Bartkova12, Irina Gromova13, Miguel Andújar-Sánchez14, Jiri Bartek12, Massimo Lopes4, Haico van Attikum3, Piet Borst9, Jos Jonkers15, Sven Rottenberg16.
Abstract
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.Entities:
Keywords: BRCA1; BRCA2; PARG; PARP inhibitor; PARP1; PARylation; drug resistance; homologous recombination; replication fork
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Year: 2018 PMID： 29894693 DOI： 10.1016/j.ccell.2018.05.008
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743